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Pyroptosis is closely involved in the pathopoiesis of cerebral ischemia and reperfusion (I/R) injury which seriously dangers human's life. Studies report that tangeretin (TANG), which is enriched in the peel of Citrus reticulata, has neuroprotective effects. Here, we explored whether absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis is involved in the cerebral I/R injury and the protective mechanism of TANG against cerebral I/R injury. In this study, we found that TANG treatment effectively alleviated I/R-induced brain injury and inhibited neuronal pyroptosis in an in vivo mice model with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and in an in vitro hippocampal HT22 cell model with oxygen–glucose deprivation and reoxygenation (OGD/R) injury. Furthermore, we found TANG inhibited cerebral I/R-induced neuronal AIM2 inflammasome activation in vivo and in vitro via regulating nuclear factor E2-related factor 2 (NRF2). Moreover, administration of ML385, a chemical inhibitor of NRF2, notably blocked the neuroprotective effects of TANG against cerebral I/R injury. In conclusion, TANG attenuates cerebral I/R-induced neuronal pyroptosis by inhibiting AIM2 inflammasome activation via regulating NRF2. These findings indicate TANG is a potential therapeutic agent for cerebral I/R injury. [ABSTRACT FROM AUTHOR]

The neuro-inflammation is well known to be an inflammatory response in the brain tissue. Anti-inflammatory therapy in ischemia/reperfusion (I/R) pathogenesis is a potential therapeutic strategy for post-I/R injury. Currently, we made attempt to scrutinize the neuro-protective effect of tangeretin against I/R injury in the brain of experimental rats. I/R injury is induced in the brain via transient middle cerebral artery occlusion (2 h) and reperfusion (20 h). The infarction area, brain water content and neurofunctional parameters were also estimated. Inflammatory cytokines and brain injury markers were scrutinized at the end of the study. mRNA expression of interleukin 6 (IL-6), toll-like receptor-4 (TLR-4), interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), interferon-γ (IFNG-γ), and transforming growth factor-β1 (TGF-β1) was estimated using the qRT-PCR. Tangeretin significantly (P < 0.001) decreased brain water content, infarct volume, neurological score, brain edema, and Evans blue leakage. Tangeretin significantly (P < 0.001) down-regulated the inflammatory and pro-inflammatory cytokines and oxidative stress parameters in the serum and brain tissue of experimental rats. qRT-PCR data demonstrated that rats treated with tangeretin could significantly (P < 0.001) suppress the IL-1β, TLR-4 TNF-α, IFNG-γ, and IL-6 and boost the expression of TGF-β1 compared with I/R injury rats. The result clearly showed tangeretin neuro-protective and anti-inflammatory effect against I/R injury in rats through suppressed inflammatory reaction. [ABSTRACT FROM AUTHOR]